The inhalation toxicity of inspired materials is critically dependent on their inhalation dosimetric patterns; this may be particularly true for the vapors derived from artificial butter flavorings. Although generally recognized as safe as food additives, exposure of workers to these vapors is associated with bronchiolitis obliterans. It has recently been shown that inhalation exposure of the rat to butter flavoring vapors results in necrosis of the nasal, bronchial and bronchiolar airways. Exposure to diacetyl (2,3 butadiene), a major component of butter flavoring vapors, results in necrosis of the nasal and trachea, but not the intrapulmonary airways. Diacetyl is metabolized by dicarbonyl reductase, an enzyme that is expressed in human and rodent respiratory tissues. Butyric acid, another major component of butter flavoring vapors, is a potent inhibitor of dicarbonyl reductase. As for other weak organic acids, it is likely that butyric acid deposits efficiently in the upper respiratory tract. Nasal metabolism is known to enhance uptake of inspired metabolized vapors, inhibition of nasal metabolism diminishes uptake in that site. This small grant proposal is aimed at characterizing upper respiratory tract uptake of diacetyl and testing the hypothesis that co-exposure to butyric acid vapor results in diminished upper respiratory tract uptake and enhanced penetration of inspired diacetyl to the target site- the lower airways. To achieve these aims uptake of diacetyl will be measured in the surgically isolated upper respiratory tract of the anesthetized rat at a variety of inspiratory flow rates and inspired concentrations, the effects of co-exposure to butyric acid on nasal diacetyl uptake will be examined, and the ability of butyric acid to inhibit nasal diacetyl metabolism in vitro will be assessed. The proposed research will provide much information that will significantly enhance our ability to quantitatively assess the risks associated with diacetyl/butter flavoring vapors, but the primary health significance lies in the use of this example to examine a novel metabolically-based mechanism for inspired vapor-vapor interactions. The URT is a metabolically competent organ expressing many xenobiotic metabolizing systems; such vapor-vapor interaction mechanisms could have relevance to a wide variety of air pollutants. Thus, in the long term, the proposed studies have the potential to enhance our ability to understand and perhaps more importantly, predict, toxicologically relevant vapor-vapor interactions that may occur during complex real world exposure scenarios. [unreadable] [unreadable]